The primary focus of our research is to define the factors and signal transduction pathways involved in the modulation of human monocyte functions that may contribute to the immunopathology associated with various disease states. Connective tissue destruction is associated with many diseases in which the monocyte/macrophage is a prominent cell. Since matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) are believed to play a major role in the destruction and remodeling of connective tissue, a major emphasis has been placed on how these enzymes and inhibitors are regulated. To address this question we are examining how biological mediators, such as cytokines, lipids and gram-negative bacteria, influence the signal transduction pathways leading to monocyte MMP and TIMP production. Current studies have shown that: (a) IFN-gamma in the presence of GM-CSF and/or TNF-alpha differentially regulates monocyte MMPs through induction of TNF-alpha and a novel mechanism involving caspase 8, (b) the ratio of LDL to HDL is critical in determining the production of MMPs by monocytes at an inflammatory site,(c) angiotensin II is an important mediator of monocyte MMP production and (d) monocyte chemoattractant protein-1 A (2518) G polymorphism is associated with occult ischemia when accompanied by greater than three coronary heart disease risk factors.